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PubMed1995

Use of a marked erythropoietin gene for investigation of its cis-acting elements.

To examine the function of conserved noncoding regions in the erythropoietin (Epo) gene, we have prepared clones and pools of Hep3B cells stably transfected with a marked 4.1-kilobase Epo gene and deletions thereof. The marked transcripts had single base substitutions at three sites in the coding portion of Exon 5, enabling them to be distinguished from endogenous Epo mRNA by ribonuclease protection and competitive polymerase chain reaction. The basal expression and hypoxic induction of the marked Epo gene that had no deletions were indistinguishable from that of the endogenous Epo gene. Likewise, deletion of conserved intervening sequence 1 had minimal effect on hypoxic induction. In contrast, a 3'-deletion that included the conserved 3'-enhancer element resulted in a substantial, but not complete, suppression of hypoxic induction while a 3'-deletion downstream of the enhancer resulted in enhancement. A 188-base pair deletion of a conserved 3'-untranslated region in Exon 5 had minimal effect on hypoxic induction. However, the truncated Epo mRNA had a markedly prolonged half-life (15 h) in comparison to the endogenous Epo mRNA (2.0 h) or the marked full-length Epo mRNA (2.1 h). Further deletions in the 3'-UTR showed that a relatively small region of approximately 50 bases is responsible for the relatively rapid turnover of Epo mRNA. These experiments provide information on cis-acting elements of the Epo gene that cannot be obtained from conventional reporter gene transfection experiments.

Base Sequence↗

PubMed2002

The proportion of cells with functional X disomy is associated with the severity of mental retardation in mosaic ring X Turner syndrome females.

Turner syndrome females (45,X) do not have mental retardation (MR), whereas some mosaic ring X Turner syndrome females, with 45,X/46,X,r(X), have severe MR. The MR is believed to be caused by a failure of X chromosome inactivation (XCI) of the small ring X chromosome, which leads to functional X disomy (FXD), To explore this hypothesis, we examined the proportion of FXD cells in the peripheral blood of four ring X Turner syndrome females with various levels of MR, using two newly developed XCI assays based on DNA methylation of X-linked genes. As a result, the two patients with extremely severe MR showed complete FXD patterns, whereas the remaining two patients with relatively milder MR showed partial FXD patterns. These results indicate that the proportion of FXD cells may be associated with the severity of MR in mosaic ring X Turner syndrome females, although this association should be confirmed by examining brain cells during development. One of the cases with severe MR and a complete FXD pattern neither lacked the XIST gene nor had uniparental X isodisomy, and we discuss the mechanism of the failure of XCI in this case.

Child↗

PubMed1987

Length mutations in human mitochondrial DNA: direct sequencing of enzymatically amplified DNA.

A specific segment of mitochondrial DNA from 18 people was examined by two methods of direct DNA sequencing. This segment includes a small noncoding region (V) shown before by restriction analysis to exhibit length polymorphism. All 11 of the human mtDNAs previously reported to have a deletion in this region proved to lack one of the two adjacent copies of a 9-base-pair sequence normally present in human mtDNAs. Phylogenetic analysis suggests that this deletion occurred only once during the evolution of modern types of human mtDNA and that it will be a valuable anthropological marker for peoples of East Asian origin. The one human mtDNA reported to have an addition in region V differs from the wild type by two mutations in the first copy of the 9-base-pair sequence: one transition and an addition of four cytosines, thereby producing a run of 11 cytosines. One of the direct DNA sequencing methods uses a single oligonucleotide primer to facilitate dideoxy sequencing from purified mtDNA templates. The second, more successful, method first amplifies this mtDNA segment enzymatically with two flanking primers (the "polymerase chain reaction") and then uses a third primer for DNA sequencing. This latter method, which works on the DNA extracted from small amounts of blood as well as on purified mtDNA, is shown to be a rapid means of defining sequence variants without purifying and cloning the same DNA segment from many individuals.

Base Sequence↗

PubMed1989

Construction of less neurovirulent polioviruses by introducing deletions into the 5' noncoding sequence of the genome.

Viral attenuation may be due to lowered efficiency of certain steps essential for viral multiplication. For the construction of less neurovirulent strains of poliovirus in vitro, we introduced deletions into the 5' noncoding sequence (742 nucleotides long) of the genomes of the Mahoney and Sabin 1 strains of poliovirus type 1 by using infectious cDNA clones of the virus strains. Plaque sizes shown by deletion mutants were used as a marker for rate of viral proliferation. Deletion mutants of both the strains thus constructed lacked a genome region of nucleotide positions 564 to 726. The sizes of plaques displayed by these deletion mutants were smaller than those by the respective parental viruses, although a phenotype referring to reproductive capacity at different temperatures (rct) of viruses was not affected by introduction of the deletion. Monkey neurovirulence tests were performed on the deletion mutants. The results clearly indicated that the deletion mutants had much less neurovirulence than with the corresponding parent viruses. Production of infectious particles and virus-specific protein synthesis in cells infected with the deletion mutants started later than in those infected with the parental viruses. The rate at which cytopathic effect progressed was also slower in cells infected with the mutants. Phenotypic stability of the deletion mutant for small-plaque phenotype and temperature sensitivity was investigated after passaging the mutant at an elevated temperature of 37.5 degrees C. Our data strongly suggested that the less neurovirulent phenotype introduced by the deletion is very stable during passaging of the virus.

Animals↗

PubMed2007

The AAA+ protein ATAD3 has displacement loop binding properties and is involved in mitochondrial nucleoid organization.

Many copies of mammalian mitochondrial DNA contain a short triple-stranded region, or displacement loop (D-loop), in the major noncoding region. In the 35 years since their discovery, no function has been assigned to mitochondrial D-loops. We purified mitochondrial nucleoprotein complexes from rat liver and identified a previously uncharacterized protein, ATAD3p. Localization studies suggested that human ATAD3 is a component of many, but not all, mitochondrial nucleoids. Gene silencing of ATAD3 by RNA interference altered the structure of mitochondrial nucleoids and led to the dissociation of mitochondrial DNA fragments held together by protein, specifically, ones containing the D-loop region. In vitro, a recombinant fragment of ATAD3p bound to supercoiled DNA molecules that contained a synthetic D-loop, with a marked preference over partially relaxed molecules with a D-loop or supercoiled DNA circles. These results suggest that mitochondrial D-loops serve to recruit ATAD3p for the purpose of forming or segregating mitochondrial nucleoids.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2007

The genetics of bipolar affective disorder.

PURPOSE OF REVIEW: Molecular genetic studies of bipolar affective disorder are beginning to show some positive and reproducible findings. The most relevant of these will be reviewed. RECENT FINDINGS: Obtaining consistent findings from whole genome scans has been hampered by small sample sizes and phenotypic heterogeneity. Recently, there have been concerted efforts to overcome these problems by combining data for meta-analysis. What has become increasingly clear is that several regions that are likely to contain genes contributing to bipolar affective disorder are also relevant to schizophrenia, a finding supported by recent twin data. Studies to date have implicated the D-amino acid oxidase activator complex (also known as G72/G30), disrupted in schizophrenia-1 and neuregulin, and have pointed to several promising linkage regions in which the genes have not yet been identified. In addition, there is some evidence to support the involvement of genetic variants in catechol-o-methyl transferase and brain-derived neurotrophic factor in the aetiology of bipolar affective disorder. SUMMARY: Molecular genetic research in bipolar affective disorder may lead to the development of new diagnostic paradigms for classifying the psychoses and affective states. In addition, determining the functional significance of the susceptibility genes will pave the way for enhanced diagnostic accuracy and improved treatments.

Amino Acid Oxidoreductases↗

PubMed2001

The complete mitochondrial genome of the articulate brachiopod Terebratalia transversa.

We sequenced the complete mitochondrial DNA (mtDNA) of the articulate brachiopod Terebratalia transversa. The circular genome is 14,291 bp in size, relatively small compared with other published metazoan mtDNAs. The 37 genes commonly found in animal mtDNA are present; the size decrease is due to the truncation of several tRNA, rRNA, and protein genes, to some nucleotide overlaps, and to a paucity of noncoding nucleotides. Although the gene arrangement differs radically from those reported for other metazoans, some gene junctions are shared with two other articulate brachiopods, Laqueus rubellus and Terebratulina retusa. All genes in the T. transversa mtDNA, unlike those in most metazoan mtDNAs reported, are encoded by the same strand. The A+T content (59.1%) is low for a metazoan mtDNA, and there is a high propensity for homopolymer runs and a strong base-compositional strand bias. The coding strand is quite G+T-rich, a skew that is shared by the confamilial (laqueid) species L. rubellus but is the opposite of that found in T. retusa, a cancellothyridid. These compositional skews are strongly reflected in the codon usage patterns and the amino acid compositions of the mitochondrial proteins, with markedly different usages being observed between T. retusa and the two laqueids. This observation, plus the similarity of the laqueid noncoding regions to the reverse complement of the noncoding region of the cancellothyridid, suggests that an inversion that resulted in a reversal in the direction of first-strand replication has occurred in one of the two lineages. In addition to the presence of one noncoding region in T. transversa that is comparable with those in the other brachiopod mtDNAs, there are two others with the potential to form secondary structures; one or both of these may be involved in the process of transcript cleavage.

Amino Acid Sequence↗

PubMed1991

The synaptophysin-encoding gene in rat and man is specifically transcribed in neuroendocrine cells.

Synaptophysin (SY) is an integral membrane protein of presynaptic small (30-80-nm) translucent vesicles also present in dispersed neuroendocrine cells. As the occurrence of this type of vesicle is specific for two major pathways of differentiation, the neuronal and neuroendocrine-epithelial information on the regulation of SY synthesis should contribute to an understanding of regulatory principles common to both pathways. Isolation and comparison of the complete rat and human single-copy genes showed that despite the difference in size (16 kb in rat vs. 13 kb in man) intron/exon boundaries are precisely conserved. Surprisingly, intron VI is located in the 3'-noncoding region in both species. The major transcriptional start point, as determined by primer extension and S1-nuclease protection analyses in rat pheochromocytoma-derived PC12 cells and rat brain, mapped to a site 27 nt 5' of the first methionine codon. Unexpectedly, the 5' upstream region is devoid of any TATA or CAAT boxes, but shows instead typical features of 'housekeeping' genes, i.e., G + C-rich islands and four Sp1-binding motifs. Using 'nuclear run-on' assays, we have identified examples in which SY synthesis is regulated at the transcriptional level. Reporter gene constructs showed that approx. 1.2 kb of the immediate upstream region contains promoter enhancer elements that were, however, insufficient to confer cell-type specific expression, whereas sequences farther upstream were able to suppress thymidine kinase promoter activity in a cell-type-dependent fashion.

Amino Acid Sequence↗

PubMed2001

Kabuki syndrome-like features associated with a small ring chromosome X and XIST gene expression.

Although clinical features in Kabuki syndrome (KS; Niikawa-Kuroki syndrome) have been well defined, the underlying genetic mechanism still remains unclear. We report a 9-year-old girl with typical KS-like facial appearance, skeletal and dermatoglyphic abnormalities, severe mental retardation, and growth deficiency. In 60 of 100 GTG-banded metaphases from peripheral blood lymphocytes, a ring chromosome smaller than a G group chromosome was found, which, according to reverse painting, consisted of Xq11.1q13. The proband's karyotype was described as mos45,X/46,X,+r(X). Several loci were analyzed with fluorescence in situ hybridization (FISH) and microsatellite markers revealing that one r(X) breakpoint mapped proximal to DXS422 (Xp11.21) and the second mapped distal to XIST gene, between loci DXS128E and DXS441 (Xq13.2). Uniparental disomy for X and r(X) was excluded and the paternal origin of r(X) was identified. XIST expression was demonstrated by nested reverse transcription polymerase chain reaction (RT-PCR) using primers spanning exons 5, 6i, and 6 in RNA prepared from lymphocytes. The observation of XIST expression is in contrast to two other cases in which the XIST gene was either not present on r(X) or not expressed. To our knowledge, this is the first case of Kabuki-like syndrome manifestations with r(X) and XIST expression.

Abnormalities, Multiple↗

PubMed2006

Molecular mechanisms for the variation of mitochondrial gene content and gene arrangement among chigger mites of the genus Leptotrombidium (Acari: Acariformes).

The gene content of a mitochondrial (mt) genome, i.e., 37 genes and a large noncoding region (LNR), is usually conserved in Metazoa. The arrangement of these genes and the LNR is generally conserved at low taxonomic levels but varies substantially at high levels. We report here a variation in mt gene content and gene arrangement among chigger mites of the genus Leptotrombidium. We found previously that the mt genome of Leptotrombidium pallidum has an extra gene for large-subunit rRNA (rrnL), a pseudo-gene for small-subunit rRNA (PrrnS), and three extra LNRs, additional to the 37 genes and an LNR typical of Metazoa. Further, the arrangement of mt genes of L. pallidum differs drastically from that of the hypothetical ancestor of the arthropods. To find to what extent the novel gene content and gene arrangement occurred in Leptotrombidium, we sequenced the entire or partial mt genomes of three other species, L. akamushi, L. deliense, and L. fletcheri. These three species share the arrangement of all genes with L. pallidum, except trnQ (for tRNA-glutamine). Unlike L. pallidum, however, these three species do not have extra rrnL or PrrnS and have only one extra LNR. By comparison between Leptotrombidium species and the ancestor of the arthropods, we propose that (1) the type of mt genome present in L. pallidum evolved from the type present in the other three Leptotrombidium species, and (2) three molecular mechanisms were involved in the evolution of mt gene content and gene arrangement in Leptotrombidium species.

Animals↗

PubMed1986

Genetic analysis of the attenuation phenotype of poliovirus type 1.

Seven different recombinant viruses from the virulent Mahoney and the attenuated Sabin parental strains of type 1 poliovirus were constructed in vitro by using infectious cDNA clones. Monkey neurovirulence tests (lesion score, spread value, and incidence of paralysis) using these recombinant viruses revealed that the loci influencing attenuation were spread over several areas of the viral genome, including the 5' noncoding region. In vitro phenotypic marker tests corresponding to temperature sensitivity of growth (rct marker), plaque size, and dependency of growth on bicarbonate concentration (d marker) were performed to identify the genomic loci of these determinants and to investigate their correlation with attenuation. Determinants of temperature sensitivity mapped to many areas of the viral genome and expressed strong but not perfect correlation with attenuation. Recombinant viruses with Sabin-derived capsid proteins showed a small-plaque phenotype, and their growth was strongly dependent on bicarbonate concentration, suggesting that these determinants map to the genomic region encoding the viral capsid proteins. Plaque size and the d marker, however, were found to be poor indicators of attenuation. Moreover, virion surface characteristics such as immunogenicity and antigenicity had little or no correlation with neurovirulence. Nevertheless, viruses carrying Sabin-derived capsid proteins had an apparent tendency to exhibit less neurovirulence in tests on monkeys compared with recombinants carrying Mahoney-derived capsid proteins. Our results suggest that the extent of viral multiplication in the central nervous system of the test animals might be one of the most important factors determining neurovirulence. Moreover, we conclude that the expression of the attenuated phenotype of the Sabin 1 strain of poliovirus is the result of several different biological characteristics. Finally, none of the in vitro phenotypic markers alone can serve as a good indicator of neurovirulence or attenuation.

Animals↗

PubMed1988

Activation and transduction of c-mil sequences in chicken neuroretina cells induced to proliferate by infection with avian lymphomatosis virus.

We report that nondividing neuroretina cells from chicken embryos can be induced to proliferate following infection with Rous-associated virus type 1 (RAV-1), an avian lymphomatosis retrovirus lacking transforming genes. Multiplication of RAV-1-infected neuroretina cells is observed after a long latency period and takes place initially in a small number of cells. We also show that serial virus passaging onto fresh neuroretina cultures leads to the generation of novel mitogenic viruses containing the mil oncogene. DNA analysis indicated that RAV-1 is the only provirus detected in cells infected at virus passage 1, whereas neuroretina cells infected at subsequent virus passages harbor mil-containing proviruses. Three viruses, designated IC1, IC2, and IC3, were molecularly cloned. Restriction mapping indicated that in each virus, truncated c-mil sequences were inserted within different portions of the RAV-1 genome. In addition, IC1 and IC2 viruses have transduced novel sequences that belong to the 3' noncoding portion of the c-mil locus. All three viruses induce neuroretina cell multiplication and direct the synthesis of mil-specific proteins. Proliferation of neuroretina cells infected at passage 1 of RAV-1 was not associated with any detectable rearrangement of c-mil, when a v-mil probe was used. However, these cells expressed high levels of an aberrant 2.8-kilobase mRNA hybridizing to mil but not to a long terminal repeat probe. Therefore, transcriptional activation of a portion of c-mil could represent the initial events induced by RAV-1 infection and lead to retroviral transduction of activated c-mil sequences.

Animals↗

PubMed1989

Structure of the 5' flanking region of the gene encoding human parathyroid-hormone-related protein (PTHrP).

We have characterized a human genomic clone that contains the 5' coding and 5' flanking sequences of the human parathyroid hormone-related protein gene (PTHrP). The 5' end of the gene contains three exons separated by two small introns of 60 and 165 bp, respectively. The coding region of the PTHrP gene exhibits significant structural homology to the human parathyroid hormone gene (PTH), including the position of at least two introns. However, there is no significant nucleotide sequence homology to the PTH gene within the intragenic region nor in the flanking genomic sequences. The PTHrP gene has been localized, by chromosomal in situ hybridization to bands p11 or p12, on human chromosome 12. Analysis of the 5'-noncoding DNA reveals a complex, putative regulatory region, with multiple potential transcription start points. Nucleotide sequence analysis shows the position of one consensus TATA sequence, at -514 bp, from the start of translation whereas the other regulatory domain is located at least 1 kb further 5' to this consensus TATA sequence. Evidence from the structure of a number of cDNA clones, as well as S1 nuclease and primer extension studies supports the hypothesis that the PTHrP gene contains at least two mRNA transcription start points that define two putative regulatory domains. The result of expression from these different promoters combined with an alternative splicing event would be to produce multiple forms of PTHrP mRNA that differ in the 5'-untranslated region. This analysis of the human PTHrP gene is the first report of a PTHrP gene for any species.

Base Sequence↗

PubMed2004

MicroRNA genes are transcribed by RNA polymerase II.

MicroRNAs (miRNAs) constitute a large family of noncoding RNAs that function as guide molecules in diverse gene silencing pathways. Current efforts are focused on the regulatory function of miRNAs, while little is known about how these unusual genes themselves are regulated. Here we present the first direct evidence that miRNA genes are transcribed by RNA polymerase II (pol II). The primary miRNA transcripts (pri-miRNAs) contain cap structures as well as poly(A) tails, which are the unique properties of class II gene transcripts. The treatment of human cells with alpha-amanitin decreased the level of pri-miRNAs at a concentration that selectively inhibits pol II activity. Furthermore, chromatin immunoprecipitation analyses show that pol II is physically associated with a miRNA promoter. We also describe, for the first time, the detailed structure of a miRNA gene by determining the promoter and the terminator of mir-23a approximately 27a approximately 24-2. These data indicate that pol II is the main, if not the only, RNA polymerase for miRNA gene transcription. Our study offers a basis for understanding the structure and regulation of miRNA genes.

3' Untranslated Regions↗

PubMed1998

Splice-site mutations: a novel genetic mechanism of Crigler-Najjar syndrome type 1.

Crigler-Najjar syndrome type 1 (CN-1) is a recessively inherited, potentially lethal disorder characterized by severe unconjugated hyperbilirubinemia resulting from deficiency of the hepatic enzyme bilirubin-UDP-glucuronosyltransferase. In all CN-1 patients studied, structural mutations in one of the five exons of the gene (UGT1A1) encoding the uridinediphosphoglucuronate glucuronosyltransferase (UGT) isoform bilirubin-UGT1 were implicated in the absence or inactivation of the enzyme. We report two patients in whom CN-1 is caused, instead, by mutations in the noncoding intronic region of the UGT1A1 gene. One patient (A) was homozygous for a G-->C mutation at the splice-donor site in the intron, between exon 1 and exon 2. The other patient (B) was heterozygous for an A-->G shift at the splice-acceptor site in intron 3, and in the second allele a premature translation-termination codon in exon 1 was identified. Bilirubin-UGT1 mRNA is difficult to obtain, since it is expressed in the liver only. To determine the effects of these splice-junction mutations, we amplified genomic DNA of the relevant splice junctions. The amplicons were expressed in COS-7 cells, and the expressed mRNAs were analyzed. In both cases, splice-site mutations led to the use of cryptic splice sites, with consequent deletions in the processed mRNA. This is the first report of intronic mutations causing CN-1 and of the determination of the consequences of these mutations on mRNA structure, by ex vivo expression.

Adult↗

PubMed2005

Genetic variants of the human dipeptide transporter PEPT1.

We tested whether genetic polymorphisms affect activity of the dipeptide transporter PEPT1, which mediates bioavailability of peptidomimetic drugs. All 23 exons and adjoining intronic sections of PEPT1 (SLC15A1) were sequenced in 247 individuals of various ethnic origins (Coriell collection). Of 38 single nucleotide polymorphisms (SNPs), 21 occurred in intronic and noncoding regions and 17 in exonic coding region, of which nine were nonsynonymous. Eight nonsynonymous variants were cloned into expression vectors and functionally characterized after transient transfection into Cos7 and Chinese hamster ovary cells. None of the variants had altered transport activity for various ligands, supporting previous results, except for the new, low-frequency PEPT1-F28Y. This variant displayed significantly reduced cephalexin uptake attributable to increased K(m). Altered pH dependence of substrate transport suggested a role for F28Y in H(+)-driven translocation. Haplotype analysis revealed significant differences among ethnic populations. To search for cis-acting polymorphisms affecting transcription and mRNA processing, we measured allelic PEPT1 mRNA expression in human intestinal biopsy samples using a frequent-marker SNP in exon 17. Of 24 heterozygous samples, significant differences in allelic mRNA levels of 20 to 30% were observed in seven tissues. However, the small difference suggests that cis-acting regulatory factors have only limited effects on transporter activity. We also measured the relative formation of a splice variant (PEPT1-RF). PEPT1-RF mRNA levels ranged from 2 to 44% of total PEPT1-related mRNA, with potential consequences for drug absorption. Together with previous results, this study reveals a relatively low level of genetic variability in polymorphisms affecting both protein function and gene regulation.

Animals↗

PubMed1985

Activation of the c-myc oncogene by the immunoglobulin heavy-chain gene enhancer after multiple switch region-mediated chromosome rearrangements in a murine plasmacytoma.

Presented is a detailed molecular analysis of the rearranged c-myc oncogene from ABPC45, an unusual plasmacytoma that was originally classified as translocation-negative. Previous data obtained by high-resolution chromosome banding suggested that this tumor was a member of a small group distinguished by the absence of rcpt (12;15) or (6;15) and further characterized by a band deletion near the c-myc locus on chromosome 15. However, genomic Southern blotting and analysis of the cloned oncogene in the present study reveal that (i) chromosome 12 sequences lie 365 base pairs 5' of the rearranged c-myc; (ii) this DNA consists of immunoglobulin alpha switch region and 5' immunoglobulin mu switch region sequences that are rearranged in an aberrant fashion; and (iii) the immunoglobulin heavy-chain gene enhancer element now resides approximately 2.5 kilobase pairs 5' of c-myc. We infer from these and other data that the rearrangement of c-myc in ABPC45 occurred via a multistep switch region-mediated process and that a reciprocal translocation has indeed taken place. Unlike many other plasmacytomas, this event did not interrupt the normal c-myc transcription unit. Rather, disruption of gene regulation is manifested in part by a change in relative usage of the two promoters normally used by the unrearranged gene. In contrast to several of its counterparts in Burkitt lymphomas, DNA sequence analysis of the translocated c-myc gene of ABPC45 reveals that it has not acquired point mutations in the noncoding first exon. These results strongly imply that a cis-acting regulatory element normally located 5' of exon 1 is lost and that heavy-chain constant region or enhancer sequences exert similar cis effects on translocated c-myc loci.

Animals↗

PubMed2026

Micropeptides encoded by lncRNAs associated with cancer progression reveal novel immunogenic epitopes.

MOTIVATION: Long non-coding RNAs (lncRNAs) regulate gene expression, chromatin organization, and cellular signaling. Recent studies indicate that ∼20% of the ∼36 000 human lncRNA genes harbor small open reading frames (sORFs) capable of producing micropeptides (MPs), whose functions remain largely unknown. Whether these peptides contribute to the cancer immunopeptidome is largely unexplored. RESULTS: We systematically analyzed lncRNAs with strong experimental and computational evidence of MP-encoding potential (∼13% of the initial MP collection). Using The Cancer Genome Atlas (TCGA), we identified 2606 high-confidence lncRNA-derived MPs encoded by 647 genes across 16 cancer types. We then focused on 501 MPs from 124 lncRNA genes whose expression changes significantly across tumor stages and metastatic transitions, representing cancer transitional lncRNAs (Tr-lncRNAs). Dipeptide composition and conservation analyses showed that these MPs differ from a size-matched human coding proteome, supporting their potential as neoantigens. All possible 9-mer peptides were evaluated for predicted binding to prevalent European HLA class I alleles. Approximately 60% of Tr-lncRNA genes and 184 (37%) of derived peptides exhibited strong predicted HLA binding. Peptides from XIST, PCAT7, PVT1, HAND2-AS1 showed broad HLA coverage. Notably, TTN-AS1, encoded an MP (79 aa) generated 33 predicted distinct epitopes spanning all 27 HLA alleles. Our analysis identifies lncRNA-derived MPs as a previously underexplored source of potential cancer neoantigens, highlighting their promise as biomarkers and targets for immunotherapy. AVAILABILITY: Data, code and supplementary materials are available in https://doi.org/10.5281/zenodo.20167452 and GitHub: https://github.com/stavzok1/lncrna_peptide_analysis.

Humans↗